homocystinuria

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homocystinuria[MeSH Terms]

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Homocystinuria

Homocystinuria is a group of autosomal recessive inborn errors of metabolism characterized by elevated homocysteine in blood and urine. The most common form - classic homocystinuria - results from deficiency of cystathionine β-synthase (CBS), a pyridoxal phosphate (PLP/B6)-dependent enzyme in the trans-sulfuration pathway.

Metabolic Pathways

The diagram below shows the full sulfur amino acid metabolic network and the key enzymatic defects:

Sulfur amino acid metabolism and homocystinuria pathway

Sulfur amino acid metabolism showing the trans-sulfuration and re-methylation pathways. Defects in CBS (trans-sulfuration) or remethylation enzymes (MTHFR, methionine synthase, cobalamin pathways) all cause elevated homocysteine. - Tietz Textbook of Laboratory Medicine, 7th ed.

The blocked reaction in classic homocystinuria:

CBS enzyme deficiency - homocysteine to cystathionine reaction

CBS condenses homocysteine + L-serine → cystathionine, requiring PLP as cofactor. A block here causes homocysteine accumulation and cysteine deficiency. - Lippincott Biochemistry, 8th ed.

Causes / Classification

At least 7 genetic disorders can cause homocystinuria. The main categories are:

Category	Defect	Effect on Methionine
Trans-sulfuration	CBS deficiency (classic)	Methionine ELEVATED
Re-methylation - folate	MTHFR deficiency	Methionine low/normal
Re-methylation - cobalamin	Methylcobalamin defects (cblC, D, E, G)	Methionine low/normal

Classic CBS deficiency is the most prevalent; worldwide incidence ~1:300,000 live births (up to 1:1,800 in Qatar).

Pathophysiology

CBS normally condenses homocysteine + serine → cystathionine (transsulfuration pathway)
CBS deficiency causes homocysteine to accumulate, methionine to rise, and cysteine to become conditionally essential
Excess homocysteine damages endothelium, activates platelets, and promotes thrombus formation
Homocysteine interferes with collagen cross-linking → skeletal and connective tissue abnormalities
Reduced cysteine lowers glutathione → increased oxidative stress

Clinical Features (Classic CBS Deficiency)

Four major systems are affected:

1. Ocular

Downward ectopia lentis (lens dislocation - inferiorly) - pathognomonic
Myopia, iridodonesis (tremulous iris)
Contrast with Marfan syndrome: lens dislocates superiorly in Marfan

2. Skeletal (Marfanoid Habitus)

Tall, slender build with long limbs
Arachnodactyly (long, spidery fingers and toes)
Scoliosis, kyphosis, pectus excavatum
Osteoporosis (not seen in Marfan)
Knock-knees, highly arched feet
Stiff joints (in contrast to Marfan's hypermobile joints)

3. Vascular

Thromboembolic episodes - the major cause of morbidity and mortality
Affects arteries and veins; can occur even in children
Thickening/fibrosis of coronary, cerebral, and renal arteries
Risk of stroke, myocardial infarction (some patients die of coronary occlusion in adolescence)

4. Neurological / Psychiatric

Intellectual disability (mild-moderate) - key differentiator from Marfan syndrome
Seizures
Psychiatric disturbances

Dermatological

Sparse, brittle, blond hair
Malar flush
Livedo reticularis

Homocystinuria vs. Marfan Syndrome

Feature	Homocystinuria	Marfan Syndrome
Inheritance	Autosomal recessive	Autosomal dominant
Lens dislocation	Downward (inferior)	Upward (superior)
Joints	Stiff	Hypermobile
Osteoporosis	Present	Absent
Intellectual disability	Common	Absent
Vascular	Thrombosis	Aortic dissection/dilation
Gene	CBS	FBN1 (fibrillin-1)

Diagnosis

Cyanide-nitroprusside test - urine screening; detects elevated urinary homocysteine (positive purple color)
Plasma amino acids - elevated methionine + homocysteine (classic CBS deficiency); low/normal methionine in remethylation defects
Total plasma homocysteine - markedly elevated (>50 µM suggests a genetic disorder; normal <15 µM); measured by immunoassay, HPLC, or MS/MS
CBS gene analysis - confirms diagnosis
Newborn screening by tandem MS/MS detects elevated methionine

Treatment

Treatment depends on whether the patient is B6-responsive (roughly 50% of CBS-deficient patients):

Approach	Detail
Pyridoxine (Vit B6) - B6-responsive patients	50-500 mg/day; acts as CBS coenzyme; milder phenotype, later onset
Low-methionine diet	Restricts substrate for homocysteine production
Cystine supplementation	Cysteine becomes essential; also replenishes glutathione
Betaine	Alternative methyl donor; promotes remethylation of homocysteine → methionine via betaine:homocysteine methyltransferase
Folate + Vitamin B12	Enhance remethylation; particularly useful in MTHFR and cobalamin defects
Anticoagulation	If vascular lesions have occurred, prevents further thrombosis

B6-non-responsive patients require stricter dietary management and typically have earlier, more severe disease.

Other Causes of Homocystinuria

When CBS is normal but homocysteine is still elevated, consider:

MTHFR deficiency - presents with stroke, dementia, epilepsy, polyneuropathy; methionine is low/normal
Methylcobalamin pathway defects (cblC, D, E, G) - also cause megaloblastic anemia, developmental delay
Nutritional - severe B12 or folate deficiency (acquired)

Key Summary Points

Classic homocystinuria = CBS deficiency (AR), the most common cause
Biochemically: high homocysteine + high methionine in plasma and urine
Clinical tetrad: ectopia lentis (inferior) + marfanoid habitus + thromboembolism + intellectual disability
Thrombosis is the leading cause of death
~50% of CBS cases respond to pyridoxine (B6)
Differentiate from Marfan by direction of lens dislocation, osteoporosis, intellectual disability, and joint stiffness

Recent literature note: 2025-2026 reviews (PMID 40495464 and 41235668) focus on novel therapeutics targeting CBS mutations and advanced metabolic therapies (enzyme replacement, chaperones, gene therapy), but current standard-of-care as described above remains unchanged.

Sources: Tietz Textbook of Laboratory Medicine (7th ed.) | Lippincott Illustrated Reviews Biochemistry (8th ed.) | Adams and Victor's Principles of Neurology (12th ed.) | Emery's Elements of Medical Genetics and Genomics | Goldman-Cecil Medicine | Miller's Review of Orthopaedics (9th ed.)

Generate the pdf

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Running Command

ls /home/daytona/workspace/ 2>/dev/null && mkdir -p /home/daytona/workspace/homocystinuria

Writing File

~/homocystinuria/generate_pdf.py


from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, Image as RLImage
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import PageBreak
from reportlab.pdfgen import canvas
from reportlab.lib.utils import ImageReader
import urllib.request
import io
import os

OUTPUT = "/home/daytona/workspace/homocystinuria/Homocystinuria.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY   = colors.HexColor("#1a3a5c")
TEAL   = colors.HexColor("#1d7a8a")
LIGHT  = colors.HexColor("#e8f4f8")
ACCENT = colors.HexColor("#e84545")
GOLD   = colors.HexColor("#e6a817")
LGREY  = colors.HexColor("#f5f5f5")
DGREY  = colors.HexColor("#444444")
WHITE  = colors.white
BLACK  = colors.black

# ── Page template with header/footer ────────────────────────────────────────
class MyPage:
    def __init__(self, title):
        self.title = title

    def on_page(self, canv, doc):
        canv.saveState()
        w, h = A4
        # Header bar
        canv.setFillColor(NAVY)
        canv.rect(0, h - 40, w, 40, fill=1, stroke=0)
        canv.setFillColor(WHITE)
        canv.setFont("Helvetica-Bold", 13)
        canv.drawString(20, h - 26, self.title)
        # Footer
        canv.setFillColor(TEAL)
        canv.rect(0, 0, w, 22, fill=1, stroke=0)
        canv.setFillColor(WHITE)
        canv.setFont("Helvetica", 8)
        canv.drawString(20, 7, "Sources: Tietz Lab Medicine | Lippincott Biochemistry | Adams & Victor Neurology | Goldman-Cecil Medicine | Emery's Genetics")
        canv.drawRightString(w - 20, 7, f"Page {doc.page}")
        canv.restoreState()

def build_styles():
    styles = getSampleStyleSheet()

    s = {}
    s["h1"] = ParagraphStyle("h1", fontName="Helvetica-Bold", fontSize=22,
                              textColor=WHITE, leading=28, spaceAfter=4)
    s["h2"] = ParagraphStyle("h2", fontName="Helvetica-Bold", fontSize=13,
                              textColor=WHITE, leading=17, spaceAfter=2)
    s["h3"] = ParagraphStyle("h3", fontName="Helvetica-Bold", fontSize=11,
                              textColor=NAVY, leading=15, spaceBefore=8, spaceAfter=3)
    s["body"] = ParagraphStyle("body", fontName="Helvetica", fontSize=9.5,
                                textColor=DGREY, leading=14, spaceAfter=5,
                                alignment=TA_JUSTIFY)
    s["bullet"] = ParagraphStyle("bullet", fontName="Helvetica", fontSize=9.5,
                                  textColor=DGREY, leading=13, leftIndent=14,
                                  bulletIndent=4, spaceAfter=2)
    s["caption"] = ParagraphStyle("caption", fontName="Helvetica-Oblique",
                                   fontSize=8, textColor=colors.HexColor("#666666"),
                                   leading=11, alignment=TA_CENTER, spaceAfter=6)
    s["label"] = ParagraphStyle("label", fontName="Helvetica-Bold", fontSize=9,
                                 textColor=TEAL, leading=12, spaceAfter=1)
    s["sources"] = ParagraphStyle("sources", fontName="Helvetica-Oblique",
                                   fontSize=7.5, textColor=colors.HexColor("#888888"),
                                   leading=10)
    return s

def section_header(text, styles):
    """Coloured section header bar."""
    data = [[Paragraph(text, styles["h2"])]]
    t = Table(data, colWidths=[17.5*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), TEAL),
        ("LEFTPADDING", (0,0), (-1,-1), 8),
        ("RIGHTPADDING", (0,0), (-1,-1), 8),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [TEAL]),
    ]))
    return t

def download_image(url, max_w, max_h):
    try:
        req = urllib.request.Request(url, headers={"User-Agent": "Mozilla/5.0"})
        data = urllib.request.urlopen(req, timeout=10).read()
        img = RLImage(io.BytesIO(data))
        iw, ih = img.imageWidth, img.imageHeight
        ratio = min(max_w/iw, max_h/ih)
        img.drawWidth  = iw * ratio
        img.drawHeight = ih * ratio
        return img
    except Exception as e:
        print(f"  [img skip] {e}")
        return None

def build():
    sty = build_styles()
    pg  = MyPage("Homocystinuria — Clinical Reference")
    doc = SimpleDocTemplate(
        OUTPUT, pagesize=A4,
        leftMargin=1.8*cm, rightMargin=1.8*cm,
        topMargin=1.8*cm, bottomMargin=1.5*cm,
        title="Homocystinuria", author="Orris Medical"
    )

    story = []
    W = 17.5*cm  # usable width

    # ── TITLE BLOCK ──────────────────────────────────────────────────────────
    title_data = [[Paragraph("Homocystinuria", sty["h1"])],
                  [Paragraph("Inborn Error of Sulfur Amino Acid Metabolism — Complete Clinical Reference", sty["body"])]]
    title_tbl = Table(title_data, colWidths=[W])
    title_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), NAVY),
        ("LEFTPADDING",  (0,0), (-1,-1), 14),
        ("RIGHTPADDING", (0,0), (-1,-1), 14),
        ("TOPPADDING",   (0,0), (-1, 0), 14),
        ("BOTTOMPADDING",(0,-1),(-1,-1), 14),
        ("TEXTCOLOR", (0,1),(-1,1), colors.HexColor("#ccddee")),
    ]))
    story.append(title_tbl)
    story.append(Spacer(1, 10))

    # ── OVERVIEW ─────────────────────────────────────────────────────────────
    story.append(section_header("Overview", sty))
    story.append(Spacer(1, 5))
    story.append(Paragraph(
        "Homocystinuria is a group of autosomal recessive inborn errors of metabolism "
        "characterized by elevated homocysteine in blood and urine. The most common form "
        "— <b>classic homocystinuria</b> — results from deficiency of "
        "<b>cystathionine β-synthase (CBS)</b>, a pyridoxal phosphate (PLP/B6)-dependent "
        "enzyme in the trans-sulfuration pathway. At least 7 distinct genetic disorders can "
        "cause homocystinuria. Worldwide incidence of CBS deficiency is ~1:300,000 live births "
        "(up to 1:1,800 in Qatar). Normal plasma total homocysteine is <b>&lt;15 µM</b>; "
        "levels &gt;50 µM suggest an inherited metabolic disorder.", sty["body"]))
    story.append(Spacer(1, 6))

    # ── METABOLIC PATHWAY ────────────────────────────────────────────────────
    story.append(section_header("Metabolic Pathway", sty))
    story.append(Spacer(1, 5))

    img1_url = "https://cdn.orris.care/cdss_images/ee87c95e62add7dbc0dcad974256abd1fabb2d00bf2daaf4a7fdebac3dd6a04d.png"
    img1 = download_image(img1_url, W, 9*cm)
    if img1:
        story.append(img1)
        story.append(Paragraph(
            "Sulfur amino acid metabolism. Methionine transfers a methyl group during conversion "
            "to homocysteine. CBS (trans-sulfuration) deficiency raises methionine; remethylation "
            "defects (MTHFR, cobalamin pathway) cause low/normal methionine. "
            "— Tietz Textbook of Laboratory Medicine, 7th ed.", sty["caption"]))
    story.append(Spacer(1, 4))

    img2_url = "https://cdn.orris.care/cdss_images/76897b41e995b771cd6163d45eb6b4d85c250f311e415adaea63091e2e3c9f01.png"
    img2 = download_image(img2_url, 6*cm, 7*cm)
    if img2:
        story.append(img2)
        story.append(Paragraph(
            "CBS reaction: Homocysteine + L-Serine → Cystathionine (requires PLP). "
            "— Lippincott Biochemistry, 8th ed.", sty["caption"]))
    story.append(Spacer(1, 6))

    # ── CAUSES / CLASSIFICATION ───────────────────────────────────────────────
    story.append(section_header("Causes / Classification", sty))
    story.append(Spacer(1, 5))

    cause_data = [
        [Paragraph("<b>Category</b>", sty["label"]),
         Paragraph("<b>Defect</b>", sty["label"]),
         Paragraph("<b>Methionine Level</b>", sty["label"])],
        [Paragraph("Trans-sulfuration", sty["body"]),
         Paragraph("CBS deficiency (classic)", sty["body"]),
         Paragraph("ELEVATED", sty["body"])],
        [Paragraph("Re-methylation (folate)", sty["body"]),
         Paragraph("MTHFR deficiency", sty["body"]),
         Paragraph("Low / Normal", sty["body"])],
        [Paragraph("Re-methylation (cobalamin)", sty["body"]),
         Paragraph("Methylcobalamin defects (cblC, D, E, G)", sty["body"]),
         Paragraph("Low / Normal", sty["body"])],
    ]
    cause_tbl = Table(cause_data, colWidths=[4.5*cm, 8*cm, 5*cm])
    cause_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ("BACKGROUND", (0,1), (-1,1), LIGHT),
        ("BACKGROUND", (0,2), (-1,2), LGREY),
        ("BACKGROUND", (0,3), (-1,3), LIGHT),
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ("LEFTPADDING",  (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("TOPPADDING",   (0,0), (-1,-1), 5),
        ("BOTTOMPADDING",(0,0), (-1,-1), 5),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(cause_tbl)
    story.append(Spacer(1, 8))

    # ── PATHOPHYSIOLOGY ───────────────────────────────────────────────────────
    story.append(section_header("Pathophysiology (CBS Deficiency)", sty))
    story.append(Spacer(1, 5))
    path_bullets = [
        "CBS normally condenses homocysteine + serine → cystathionine (trans-sulfuration pathway).",
        "CBS deficiency causes homocysteine accumulation, methionine rise, and <b>cysteine deficiency</b> (cysteine becomes conditionally essential).",
        "Excess homocysteine damages vascular endothelium, activates platelets, and promotes thrombosis.",
        "Homocysteine interferes with collagen cross-linking → skeletal and connective tissue abnormalities.",
        "Reduced cysteine lowers glutathione → increased oxidative stress.",
        "Cystathionine (normally present in brain) is absent → may explain developmental delay.",
    ]
    for b in path_bullets:
        story.append(Paragraph(f"• {b}", sty["bullet"]))
    story.append(Spacer(1, 6))

    # ── CLINICAL FEATURES ─────────────────────────────────────────────────────
    story.append(section_header("Clinical Features — Classic CBS Deficiency", sty))
    story.append(Spacer(1, 5))

    features = [
        ("Ocular",
         ["Downward ectopia lentis (inferiorly dislocated lens) — pathognomonic",
          "Myopia, iridodonesis (tremulous iris)",
          "CONTRAST with Marfan syndrome: lens dislocates superiorly in Marfan"]),
        ("Skeletal (Marfanoid Habitus)",
         ["Tall, slender build with long limbs; arachnodactyly",
          "Scoliosis, kyphosis, pectus excavatum",
          "Osteoporosis (not seen in Marfan syndrome)",
          "Knock-knees, highly arched feet",
          "STIFF joints (contrast: Marfan has hypermobile joints)"]),
        ("Vascular",
         ["Thromboembolic episodes — major cause of morbidity and mortality",
          "Affects both arteries and veins; can occur even in children",
          "Thickening/fibrosis of coronary, cerebral, renal arteries",
          "Risk of stroke, MI (some die of coronary occlusion in adolescence)"]),
        ("Neurological / Psychiatric",
         ["Intellectual disability (mild-moderate) — key differentiator from Marfan",
          "Seizures",
          "Psychiatric disturbances, developmental delay"]),
        ("Dermatological",
         ["Sparse, brittle, blond hair",
          "Malar flush",
          "Livedo reticularis"]),
    ]

    for sys_name, bullets in features:
        story.append(Paragraph(sys_name, sty["h3"]))
        for b in bullets:
            story.append(Paragraph(f"• {b}", sty["bullet"]))
        story.append(Spacer(1, 3))
    story.append(Spacer(1, 4))

    # ── VS MARFAN ─────────────────────────────────────────────────────────────
    story.append(section_header("Homocystinuria vs. Marfan Syndrome", sty))
    story.append(Spacer(1, 5))

    marfan_data = [
        [Paragraph("<b>Feature</b>", sty["label"]),
         Paragraph("<b>Homocystinuria</b>", sty["label"]),
         Paragraph("<b>Marfan Syndrome</b>", sty["label"])],
        ["Inheritance", "Autosomal recessive", "Autosomal dominant"],
        ["Lens dislocation", "Downward (inferior)", "Upward (superior)"],
        ["Joints", "Stiff", "Hypermobile"],
        ["Osteoporosis", "Present", "Absent"],
        ["Intellectual disability", "Common", "Absent"],
        ["Vascular complication", "Thrombosis", "Aortic dissection/dilation"],
        ["Gene", "CBS (cystathionine β-synthase)", "FBN1 (fibrillin-1)"],
    ]
    marfan_data_fmt = []
    for i, row in enumerate(marfan_data):
        if i == 0:
            marfan_data_fmt.append(row)
        else:
            marfan_data_fmt.append([Paragraph(str(c), sty["body"]) for c in row])

    marfan_tbl = Table(marfan_data_fmt, colWidths=[4.5*cm, 6.5*cm, 6.5*cm])
    marfan_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        *[("BACKGROUND", (0,i), (-1,i), LIGHT if i%2==1 else LGREY) for i in range(1,8)],
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ("LEFTPADDING",  (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("TOPPADDING",   (0,0), (-1,-1), 4),
        ("BOTTOMPADDING",(0,0), (-1,-1), 4),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(marfan_tbl)
    story.append(Spacer(1, 8))

    # ── DIAGNOSIS ─────────────────────────────────────────────────────────────
    story.append(section_header("Diagnosis", sty))
    story.append(Spacer(1, 5))

    diag_data = [
        [Paragraph("<b>Test</b>", sty["label"]),
         Paragraph("<b>Finding</b>", sty["label"]),
         Paragraph("<b>Notes</b>", sty["label"])],
        ["Cyanide-nitroprusside test (urine)",
         "Purple colour = positive",
         "Screening; detects elevated urinary homocysteine"],
        ["Plasma amino acids",
         "↑ Methionine + ↑ Homocysteine",
         "Classic CBS; low/normal Met in remethylation defects"],
        ["Total plasma homocysteine",
         ">50 µM (normal <15 µM)",
         "By immunoassay, HPLC, or MS/MS"],
        ["Newborn screening (MS/MS)",
         "Elevated methionine",
         "Detects CBS deficiency early"],
        ["CBS gene analysis",
         "CBS mutation",
         "Confirms diagnosis; determines B6-responsiveness"],
    ]
    diag_fmt = []
    for i, row in enumerate(diag_data):
        if i == 0:
            diag_fmt.append(row)
        else:
            diag_fmt.append([Paragraph(str(c), sty["body"]) for c in row])

    diag_tbl = Table(diag_fmt, colWidths=[4.5*cm, 6*cm, 7*cm])
    diag_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        *[("BACKGROUND", (0,i), (-1,i), LIGHT if i%2==1 else LGREY) for i in range(1,6)],
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ("LEFTPADDING",  (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("TOPPADDING",   (0,0), (-1,-1), 4),
        ("BOTTOMPADDING",(0,0), (-1,-1), 4),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(diag_tbl)
    story.append(Spacer(1, 8))

    # ── TREATMENT ─────────────────────────────────────────────────────────────
    story.append(section_header("Treatment", sty))
    story.append(Spacer(1, 5))
    story.append(Paragraph(
        "Treatment depends on whether the patient is <b>B6-responsive</b> (~50% of CBS-deficient patients). "
        "B6-non-responsive patients require stricter dietary management and typically have earlier, more severe disease.",
        sty["body"]))
    story.append(Spacer(1, 4))

    tx_data = [
        [Paragraph("<b>Approach</b>", sty["label"]),
         Paragraph("<b>Details</b>", sty["label"])],
        ["Pyridoxine (Vit B6) — B6-responsive patients",
         "50-500 mg/day; acts as CBS coenzyme; milder phenotype with later onset"],
        ["Low-methionine diet",
         "Restricts substrate for homocysteine production"],
        ["Cystine supplementation",
         "Cysteine becomes essential; replenishes glutathione and reduces oxidative stress"],
        ["Betaine",
         "Alternative methyl donor; promotes remethylation of Hcy → methionine via betaine:homocysteine methyltransferase"],
        ["Folate + Vitamin B12",
         "Enhance remethylation; particularly useful in MTHFR and cobalamin defects"],
        ["Anticoagulation",
         "If vascular lesions have occurred; prevents further thrombotic events"],
    ]
    tx_fmt = []
    for i, row in enumerate(tx_data):
        if i == 0:
            tx_fmt.append(row)
        else:
            tx_fmt.append([Paragraph(str(c), sty["body"]) for c in row])

    tx_tbl = Table(tx_fmt, colWidths=[6.5*cm, 11*cm])
    tx_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), NAVY),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        *[("BACKGROUND", (0,i), (-1,i), LIGHT if i%2==1 else LGREY) for i in range(1,7)],
        ("GRID", (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ("LEFTPADDING",  (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("TOPPADDING",   (0,0), (-1,-1), 4),
        ("BOTTOMPADDING",(0,0), (-1,-1), 4),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]))
    story.append(tx_tbl)
    story.append(Spacer(1, 8))

    # ── OTHER CAUSES ──────────────────────────────────────────────────────────
    story.append(section_header("Other Causes of Homocystinuria / Hyperhomocysteinemia", sty))
    story.append(Spacer(1, 5))
    other = [
        "<b>MTHFR deficiency:</b> Stroke, dementia, epilepsy, polyneuropathy; methionine low/normal.",
        "<b>Methylcobalamin pathway defects (cblC, D, E, G):</b> Also cause megaloblastic anemia, developmental delay.",
        "<b>Nutritional (acquired):</b> Severe vitamin B12 or folate deficiency.",
        "<b>Mild hyperhomocysteinemia</b> (>15 µM) in otherwise normal individuals: independent cardiovascular risk factor for coronary artery disease and stroke.",
    ]
    for b in other:
        story.append(Paragraph(f"• {b}", sty["bullet"]))
    story.append(Spacer(1, 6))

    # ── KEY SUMMARY BOX ──────────────────────────────────────────────────────
    summary_items = [
        "Classic homocystinuria = CBS deficiency (autosomal recessive)",
        "Biochemistry: high homocysteine + high methionine in plasma and urine",
        "Clinical tetrad: ectopia lentis (inferior) + marfanoid habitus + thromboembolism + intellectual disability",
        "Thrombosis is the leading cause of death",
        "~50% of CBS cases respond to pyridoxine (B6)",
        "Differentiate from Marfan by: lens direction (down vs up), osteoporosis, intellectual disability, joint stiffness",
        "Screen with cyanide-nitroprusside test; confirm with plasma homocysteine + CBS gene analysis",
    ]
    summary_content = [Paragraph("Key Summary Points", sty["h2"])]
    for item in summary_items:
        summary_content.append(Paragraph(f"✓  {item}", sty["bullet"]))

    sum_data = [[c] for c in summary_content]
    sum_tbl = Table([[c] for c in [
        Paragraph("Key Summary Points", sty["h2"]),
        *[Paragraph(f"  ✓  {item}", sty["bullet"]) for item in summary_items]
    ]], colWidths=[W])
    sum_tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), GOLD),
        ("BACKGROUND", (0,1), (-1,-1), colors.HexColor("#fffbe6")),
        ("LEFTPADDING",  (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING",   (0,0), (-1, 0), 7),
        ("TOPPADDING",   (0,1), (-1,-1), 3),
        ("BOTTOMPADDING",(0,0), (-1, 0), 7),
        ("BOTTOMPADDING",(0,-1),(-1,-1), 8),
        ("BOX", (0,0), (-1,-1), 0.8, GOLD),
    ]))
    story.append(sum_tbl)
    story.append(Spacer(1, 10))

    # ── SOURCES ───────────────────────────────────────────────────────────────
    story.append(HRFlowable(width=W, thickness=0.5, color=colors.HexColor("#cccccc")))
    story.append(Spacer(1, 4))
    story.append(Paragraph(
        "Sources: Tietz Textbook of Laboratory Medicine (7th ed.) | Lippincott Illustrated Reviews: Biochemistry (8th ed.) | "
        "Adams and Victor's Principles of Neurology (12th ed.) | Goldman-Cecil Medicine | "
        "Emery's Elements of Medical Genetics and Genomics | Miller's Review of Orthopaedics (9th ed.) | "
        "Recent reviews: PMID 40495464, PMID 41235668.",
        sty["sources"]))

    doc.build(story, onFirstPage=pg.on_page, onLaterPages=pg.on_page)
    print(f"PDF written to {OUTPUT}")

build()

Running Command

cd /home/daytona/workspace/homocystinuria && python generate_pdf.py 2>&1

Running Command

ls -lh /home/daytona/workspace/homocystinuria/Homocystinuria.pdf

Your PDF is ready (457 KB):

Homocystinuria

PDF Document · PDF

The document includes:

Title block with full topic header
Metabolic pathway diagrams (both the full sulfur amino acid cycle and the CBS reaction)
Causes/Classification table (trans-sulfuration vs. remethylation defects)
Pathophysiology bullet points
Clinical Features across all 5 systems (ocular, skeletal, vascular, neurological, dermatological)
Homocystinuria vs. Marfan Syndrome comparison table
Diagnosis table (cyanide-nitroprusside, plasma amino acids, total Hcy, newborn screening, gene analysis)
Treatment table (B6-responsive vs. non-responsive, diet, betaine, folate/B12, anticoagulation)
Other causes of hyperhomocysteinemia
Key Summary Points highlighted box
Coloured header/footer with page numbers and source citations throughout

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